4-halo-21-chloropregnan-17alpha-ol-3, 11, 20-triones and preparation thereof



Patented Aug. 10, 1954 4-HALO -2 1- CHLOROPREGNAN -17a- OL- 3,11,20-TRIONES AND PREPARATION THEREOF Raymond 0. Clinton, North Greenbush, N. Y., as-

signor .to Sterling Drug Inc., New York, N. Y., a corporation of Delaware No Drawing. Application April 29, 1952,

Serial No. 285,069

6 Claims. 1

This invention relates to new chemical compounds, 4-ha1o-21-chloropregnan-17a-o1-3,11,20- triones, and to their preparation. In particular the invention relates to 4-bromo-21-chloropregnan-1'lu-ol-3,ll,20-trione and 4-iodo-21-chloropregnan-l'M-ol-il1,20-trione.

These substances are useful as intermediates in the preparation of adrenal cortical hormones. In a few steps they can be converted into the important hormone known as cortisone. This is ac complished by treating the 4-halo-21chloropregnan-17a-o1-3,l1,20-trione with hydrazine or a substituted hydrazine to remove the elements of hydrogen halide from the 4- and 5-positions, hydrolyzingthe resulting hydrazone of 21-chloro-4- pregnen-17a-ol-3,11,20-trione to 21-chloro-4- pregnen-17u-ol-3,11,20-trione, and treating the latter with a metallic acetate to produce cortisone acetate.

The 4-halo-21-chloropregnan17a-ol-3,11,20- triones are prepared by halogenation of 21- chloroprcgnan-17a-ol-3,11,20-trione in the 4-position. 21-chloropregnan-17a-01-3,11,20-trione is described in the copending application of R. 0. Clinton, Serial No. 259,510, filed December 1, 1951, now abandoned. 21'-Chloropregnan-17uol-3,11,20trione is in turn prepared by oxidation of 21 chloropregnane 3,1711 diol 11,20- dione which is described in the copending application of W. S. Johnson and R. 0. Clinton, Serial No. 253,012, filed October 24, 1951, now abandoned.

4 bromo 21 chloropregnan 17a ol- 3,11,20-trione canbe prepared by direct bromination of 21-chloropregnan-17a-ol-3,11,20-trione in the-presence of an acceptor for strong acids such as an alkali metal salt of a weak acid, for example, sodium acetate. The purpose of the latter is to take up the hydrogen bromide produced in the reaction. However this method is not very satisfactory because the yields are low and the product is difiicult to purify due to competitive side reactions dependent upon the amount of bromine used and the rate of its addition. Results are not easily duplicated because of the difiiculty of measuring quantities of elementary bromine accurately.

A preferred method for the prepartion of 4- bromo 21 chloropregnan 17oz o1 3,11,20- trione comprises treating 21-chloropregnan-17ao1-3,l1,20-trione with pyridinium bromide perbromide (pyridine hydrobromide dibromide, C5H5N.HB1.BI2). It is advantageous to use less than an equivalent amount of pyridinium bromideperbromide as it has been found to be easier to separate the desired 4-bromo-21-chloropreg- 0.05 mole, M P. 2382-2395 C.) was dissolved nan-17a-ol-3,11,20-trione from unreacted 21- chloropregnan-l7a-0l-3J1,20-trione than from the byproducts formed when a full equivalent of brominating agent is used. The unbrominated starting material is significantly less soluble in most solvents than the 4-bromo derivative, and the former can be readily recovered and recycled if desired. The reaction of the steroid with pyridinium bromide perbromide alone gives a mixture of the 2-b1'omo and 4-bromo steroids. To prevent formation of the 2-bromo isomer it is desirable to add an equivalent amount of an acid acceptor such as an alkali metal acylate, for example, sodium acetate, to take up the hydrogen bromide formed in the reaction. If the acid acceptor is added, it is necessary to add a trace of hydrogen bromide as a catalyst before introduction of the brominating agent and the acid accentor.

The bromination reaction takes place in an inert organic solvent. Appropriate solvents are well-known to the organic chemist and are those in which steroids are readily soluble and which do not themselves react with the brominating agent. Lower fatty acids are especially useful solvents, in particular acetic acid.

4 iodo 21 chloropregnan 17oz ol 3,11,20- trione is prepared by direct iodination of 21- chloropregnan-17u-ol-3,11,20-trione using elementary iodine in the presence of an epoxide, preferably of the 'glycidyl ether type,

hydrazine or a substituted hydrazine to introduce a double bond in the 4,5-position.

The following examples will further illustrate the invention.

EXAMPLE 1 4-bromo-21 -chl0ro1oregnan-1 7a-Ol-3,11,20-

trione 21-chloropregnan-17u-ol-3,11,20-trione (19.05

with stirring and heating in 950 m1. of glacial acetic acid. The solution was cooled to about 26 C. and 1.0 ml. of a 30% solution of hydrogen bromide in acetic acid was added, followed by dropwise addition with vigorous stirringover a period of two and one-half hours of a solution of 12.72 g. of pyridinium bromide perbromide (94.4%, 0.0375 mole) and 5.10 g. of sodium acetate trihydrate (0.0375 mole) in 150 ml. of acetic acid. A pale yellow solution was obtained containing some crystalline material (A) which was filtered off and washed with a little acetic acid. The combined acetic acid filtrate and washings were diluted slowly with stirring with 500 ml. portions of water until 2500 ml. of water had been added. The solid product thus obtained was collected by filtration and washed with 2000 ml. of water and dried at 70 C. to constant weight (13.95 g.) The latter material was boiled for one minute with 100 ml. of ethyl acetate, cooled in ice for fifteen minutes, and the crystallized product (B) was collected by filtration and washed with 20 ml. of cold ethyl acetate. The ethyl acetate filtrate and washings were concentrated to 40 ml. and diluted with 180 ml. of absolute ether. A further crystalline product was thus obtained which was collected by filtration, washed with ether and dried at 50 C. giving 8.75 g. of 4-bromo-2l-chloropregnan-fla-ol- 3,11,20-trione, M. P. 184-185 C. (dec.). This compound was further purified by recrystallization from dilute acetone and then from methanol followed by drying in a vacuum oven at 55 C. for seven hours, giving a sample melting at 1898-1902 C. (dec.), [a] =I-113.9 (1% in chloroform) AnaL-Calcd. for C21H23B1C1O4: C, 54.85; H. 6.14; Br, 17.38. Found: C, 55.34; H, 6.52; Br, 17.54.

The more sparingly soluble materials (A and B) collected after completion of the reaction and again during the purification stage proved to be unreacted 21-chloropregnan-17a-ol3,11,20- trione, and this could be used over again in another bromination reaction.

EXAMPLE 2 4-i0d0'21-ChZOTODTegTtCln-17ozOl-3,11,20 trione and its conversion to 21-chZ0ro-4-pregnen-17a- (ll-3,11,20-t7i01l5 3 (2,4 dinitrophenylhydrazone) A mixture of 7.62 g. (0.02 mole, M. P. 234-236 C.) of 21-chloropregnan-l7a-ol-3,11,20-trione, 5.08 g. (0.02 mole) of powdered iodine, 7.0 g. (0.06 mole) of glycidyl isopropyl ether and 100 ml. of glacial acetic acid was stirred and heated until the internal temperature reached about 110 C. The iodine uptake was complete in about five minutes, and all traces of sublimed iodine were rinsed down into the reaction mixture with 20 ml. of acetic acid. There was thus obtained a solution containing 4-iodo-21-chloropregnanl7a-ol3,11,20-trione.

The solution of 4-iodo-2l-chloropregnan-lho1-3,11,20-trione obtained above was cooled to 70 C., a nitrogen atmosphere was introduced, and 4.80 g. (0.0242 mole) of Z'A-dinitrophenylhydra- Zine was added with the aid of 100 ml. of chloroform. The mixture was refluxed under nitrogen for one hour with the internal temperature at 83-90 C. The mixture was then concentrated in vacuo to a volume of about 30 ml., 100 ml. of absolute ether was added, and the solution was cooled to C. for four hours. The resulting solid was collected by filtration and dried giving 7.65

g. of the 3-(2,4-dinitrophenylhydrazone) of 21- chloro-4-pregnen-17a-0l-3,11,20-trione, M. P. 205-207" C. (dec.). The hydrazone was recrystallized twice by dissolving it in chloroform, filtering the solution, adding acetic acid and concentrating the solution to a small volume until most of the chloroform was removed. Thus was obtained a purified sample of the 3-(2,4-dinitrophenylhydrazone) of 21-chloro-4-pregnen-17aol-3,11,20-trione, M. P. 224-2245 0., ultraviolet absorption maximum (in CHClz) E=28,649 at 384 III/1..

AnaZ.Calcd. for C2'1H31C1N407I C, 58.01; H, 5.59; N, 10.02. Found: C, 58.06; H, 5.72; N, 9.80.

EXAMPLE 3 CHzCl =0 ----0H wherein X is a member of the group consisting of bromine and iodine.

2. 4 bromo-21-chloropregnan-17e-ol-3,11.20- trione.

3. 4 iodo 21 chloropregnan-Howl-3,11,20- trione.

4. A process for preparing 4-bromo-21-chloropregnan-l7u-oI-3J1,20-trione which comprises treating 21-chloropregnan-17a-ol-3,11,20-trione in an inert organic solvent with a member of the group consisting of bromine and pyridinium bromide perbromide.

5. A process for preparing 4-bromo-21-chloropregnan-17a-ol-3,11,20-trione which comprises adding a trace of hydrogen bromide to an acetic acid solution of 2l-chloropregnan-Heal-3,11,20- trione and adding slightly less than equivalent amounts of pyridinium bromide perbrom'ide' and an alkali metal acylate'.

6. A process for preparing 4-iodo 21-chloropregnan-lh-ol-sd1,20-trione which comprises heating 21-chloropregnan-17a-ol-3,1l,20-trione with about one equivalent of elementary iodine in an inert polar organic solvent in the presence of an epoxide having the formula no onion- 011,

wherein R. is a hydrocarbon radical having from 1 to 8 carbon atoms.

Preferences Cit-ed in the file of this patent UNITED STATES PATENTS Number Name Date 2,401,775 Reichstein 1.. June 11-, 1.946 2541.104 Sarett Feb. 13, 1951 

1. A COMPOUND HAVING THE FORMULA 